Abstract 347: TET1 mutation as potential biomarker for immune checkpoint blockade in colorectal cancer

Abstract

Abstract Background: TET1, a DNA demethylase, is encoded by TET1 gene. At present, TET1 mutation has been reported to be associated with enhanced tumor immunogenicity and activated anti-tumor immunity across multiple cancers. However, the clinical effect of TET1 mutation on immunotherapy in colorectal cancer is little known. Methods: 876 patients with colorectal cancer were enrolled in this study. Genomic profiling of DNA was performed on formalin-fixed paraffin-embedded tumor samples by NGS with 733 cancer-related genes panel. The somatic and germline mutation data were both obtained. Benign and likely benign mutations were excluded from our analysis. Programmed death ligand-1(PD-L1) expression status was determined by immunohistochemistry, evaluated with the combined positive score (CPS) and tumor proportion score (TPS). The efficiency of immunotherapy was analyzed in a cohort of 85 patients with colorectal cancer from Morris et al. Results: 40 of 876 patients (4.75%) harbored TET1 mutations, including nonsynonymous, frameshift and stopgain mutations. Totally, 66 TET1 single nucleotide mutation were identified. Median tumor mutation burden (TMB) value with TET1 mutations was 109.2 mutations/MB, significantly higher than 6.1 mutations/MB in TET1 wild-type group (p<0.001). Microsatellite instability-high (MSI-H) appeared more frequently in TET1 mutations group than TET1 wild-type group (50.0% vs 5.0%, p<0.001). For PD-L1 TPS, compare to TET1 wild type groups, the positive rate of PD-L1 expression in TET1 mutations was higher significantly (6.7% vs 2.7%, p<0.001). The same thing happened with PD-L1 CPS (50.0% vs 23.3%, p<0.001). Possibly, TET1 mutation was a potential marker for immunotherapy. The results were validated in a clinical cohort of immunotherapy, including 85 patients with colorectal cancer. The median overall survival was non-reached in 7 patients with TET1 mutations compare to 13 months in TET1 wild-type group (HR: 0.28, 95% CI 0.11-0.69, P=0.006). Conclusions: TET1 mutation was strongly associated with higher TMB, MSI-H and PD-L1 expression and improved OS in patients receiving immune checkpoint blockade treatment, suggesting that TET1 mutation is a novel predictive biomarker for immunotherapy in colorectal cancer. Citation Format: Shaojun Yu, Ding Zhang, Shiqing Chen. TET1 mutation as potential biomarker for immune checkpoint blockade in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 347.